title: Improved docking of polypeptides with Glide.
abstract: Predicting the binding mode of flexible polypeptides to proteins is an important task that falls outside the domain of applicability of most small molecule and protein-protein docking tools. Here, we test the small molecule flexible ligand docking program Glide on a set of 19 non-α-helical peptides and systematically improve pose prediction accuracy by enhancing Glide sampling for flexible polypeptides. In addition, scoring of the poses was improved by post-processing with physics-based implicit solvent MM-GBSA calculations. Using the best RMSD among the top 10 scoring poses as a metric, the success rate (RMSD ≤ 2.0 Å for the interface backbone atoms) increased from 21% with default Glide SP settings to 58% with the enhanced peptide sampling and scoring protocol in the case of redocking to the native protein structure. This approaches the accuracy of the recently developed Rosetta FlexPepDock method (63% success for these 19 peptides) while being over 100 times faster. Cross-docking was performed for a subset of cases where an unbound receptor structure was available, and in that case, 40% of peptides were docked successfully. We analyze the results and find that the optimized polypeptide protocol is most accurate for extended peptides of limited size and number of formal charges, defining a domain of applicability for this approach.
authors.affiliation: Schrödinger, Inc., 120 West 45th street, New York, New York 10036, USA.
authors.forename: Ivan
authors.initials: I
authors.lastname: Tubert-Brohman
authors.forename: Woody
authors.initials: W
authors.lastname: Sherman
authors.forename: Matt
authors.initials: M
authors.lastname: Repasky
authors.forename: Thijs
authors.initials: T
authors.lastname: Beuming
mesh_terms: D000465:Algorithms; D000595:Amino Acid Sequence; D001665:Binding Sites; D062313:Databases, Pharmaceutical; D062105:Molecular Docking Simulation; D010455:Peptides / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D012984:Software; D013499:Surface Properties; D013997:Time Factors
chemical_list: D010455:Peptides